tretinoin and 13-14-dihydroretinoic-acid

The identity of the endogenous RXR ligand has not been conclusively determined, even though several compounds of natural origin, including retinoids and fatty acids, have been postulated to fulfill this role. Filling this gap, 9-cis-13,14-dihydroretinoic acid (9CDHRA) was identified as an endogenous RXR ligand in mice. This review examines the physiological relevance of various potential endogenous RXR ligands, especially 9CDHRA. The elusive steps in the metabolic synthesis of 9CDHRA, as well as the nutritional/nutrimetabolic origin of 9CDHRA, are also explored, along with the suitability of the ligand to be the representative member of a novel vitamin A class (vitamin A5).

Topics: Animals; Humans; Ligands; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Retinol-Binding Proteins; Tretinoin; Vitamin A; Vitamins

Topics: Adenocarcinoma; Animals; Carcinoma, Pancreatic Ductal; Gene Expression; Humans; Ligands; Mice; Pancreas; Pancreatic Neoplasms; Receptors, Retinoic Acid; Tretinoin

The retinoid X receptors (RXRs) are ligand-activated transcription factors which heterodimerize with a number of nuclear hormone receptors, thereby controlling a variety of (patho)-physiological processes. Although synthetic RXR ligands are developed for the treatment of various diseases, endogenous ligand(s) for these receptors have not been conclusively identified. We show here that mice lacking cellular retinol binding protein (Rbp1-/-) display memory deficits reflecting compromised RXR signaling. Using HPLC-MS and chemical synthesis we identified in Rbp1-/- mice reduced levels of 9-cis-13,14-dihydroretinoic acid (9CDHRA), which acts as an RXR ligand since it binds and transactivates RXR in various assays. 9CDHRA rescues the Rbp1-/- phenotype similarly to a synthetic RXR ligand and displays similar transcriptional activity in cultured human dendritic cells. High endogenous levels of 9CDHRA in mice indicate physiological relevance of these data and that 9CDHRA acts as an endogenous RXR ligand.

Topics: Amino Acid Sequence; Animals; Chlorocebus aethiops; COS Cells; Humans; Ligands; Memory Disorders; Mice; Molecular Sequence Data; Protein Binding; Retinoid X Receptors; Retinol-Binding Proteins, Cellular; Tretinoin

Vitamin A-derived metabolites act as ligands for nuclear receptors controlling the expression of a number of genes. Stereospecific saturation of the C(13)-C(14) double bond of all-trans-retinol by the enzyme, retinol saturase (RetSat), leads to the production of (R)-all-trans-13,14-dihydroretinol. In liver and adipose tissue, expression of RetSat is controlled by peroxisome proliferator-activated receptors (PPAR) alpha and gamma, respectively. Expression of RetSat in adipose tissue is also required for PPARgamma activation and adipocyte differentiation, but the involved mechanism is poorly understood. In this study, we examined the potential of (R)-all-trans-13,14-dihydroretinol and its metabolites to control gene transcription via nuclear receptors. Using a cell-based transactivation assay to screen 25 human nuclear receptors for activation, we found that dihydroretinoids have a narrow transcriptional profile limited primarily to activation of retinoic acid receptors (RARs). Although (R)-all-trans-13,14-dihydroretinoic acid exhibited comparable potency to retinoic acid in promoting the interaction of RARs with a coactivator peptide in vitro, its potency in activating RAR-controlled genes in cell-based assays was much lower than that of retinoic acid. As an explanation for the weak RAR agonist activity of dihydroretinoids in cell-based assays, we propose that both delivery of ligand to the nucleus and RAR activation favor retinoic acid over dihydroretinoids. Discrimination between the cognate ligand, retinoic acid, and close analogs such as dihydroretinoids, occurs at multiple levels and may represent a mechanism to modulate retinoid-dependent physiological processes.

Topics: Cell Line; Humans; Receptors, Retinoic Acid; Retinol-Binding Proteins, Plasma; Spectrometry, Fluorescence; Transcriptional Activation; Tretinoin

The metabolism of vitamin A is a highly regulated process that generates essential mediators involved in the development, cellular differentiation, immunity, and vision of vertebrates. Retinol saturase converts all-trans-retinol to all-trans-13,14-dihydroretinol (Moise, A. R., Kuksa, V., Imanishi, Y., and Palczewski, K. (2004) J. Biol. Chem. 279, 50230-50242). Here we demonstrate that the enzymes involved in oxidation of retinol to retinoic acid and then to oxidized retinoic acid metabolites are also involved in the synthesis and oxidation of all-trans-13,14-dihydroretinoic acid. All-trans-13,14-dihydroretinoic acid can activate retinoic acid receptor/retinoid X receptor heterodimers but not retinoid X receptor homodimers in reporter cell assays. All-trans-13,14-dihydroretinoic acid was detected in vivo in Lrat-/- mice supplemented with retinyl palmitate. Thus, all-trans-13,14-dihydroretinoic acid is a naturally occurring retinoid and a potential ligand for nuclear receptors. This new metabolite can also be an intermediate in a retinol degradation pathway or it can serve as a precursor for the synthesis of bioactive 13,14-dihydroretinoid metabolites.

Topics: Aldehydes; Animals; Catalysis; Cell Line; Chromatography, High Pressure Liquid; Cloning, Molecular; Cytochrome P-450 Enzyme System; Dimerization; DNA, Complementary; Electrophoresis, Polyacrylamide Gel; Genes, Reporter; Humans; Hydrolysis; Liver; Mice; Models, Chemical; Oxygen; Retinoic Acid 4-Hydroxylase; Retinoid X Receptors; Retinoids; Spectrophotometry; Time Factors; Transcriptional Activation; Transfection; Tretinoin; Ultraviolet Rays; Vitamin A